Climbing fiber regulation of spontaneous Purkinje cell activity and cerebellum-dependent blink responses

It has been known for a long time that GABAergic Purkinje cells in the cerebellar cortex, as well as their target neurons in the cerebellar nuclei, are spontaneously active. The cerebellar output will, therefore, depend on how input is integrated into this spontaneous activity. It has been shown that input from climbing fibers originating in the inferior olive controls the spontaneous activity in Purkinje cells. While blocking climbing fiber input to the Purkinje cells causes a dramatic increase in the firing rate, increased climbing fiber activity results in reduced Purkinje cell activity. However, the exact calibration of this regulation has not been examined systematically. Here we examine the relation between climbing fiber stimulation frequency and Purkinje cell activity in unanesthetized decerebrated ferrets. The results revealed a gradual suppression of Purkinje cell activity, starting at climbing fiber stimulation frequencies as low as 0.5 Hz. At 4 Hz, Purkinje cells were completely silenced. This effect lasted an average of 2 min after the stimulation rate was reduced to a lower level. We also examined the effect of sustained climbing fiber stimulation on overt behavior. Specifically, we analyzed conditioned blink responses, which are known to be dependent on the cerebellum, while stimulating the climbing fibers at different frequencies. In accordance with the neurophysiological data, the conditioned blink responses were suppressed at stimulation frequencies of =4 Hz

Serum levels of autoantibodies against monomeric C-reactive protein are correlated with disease activity in systemic lupus erythematosus

This study was performed to investigate the relation between IgG autoantibodies against human C-reactive protein (anti-CRP) and disease activity measures in serial serum samples from 10 patients with systemic lupus erythematosus (SLE), of whom four had active kidney involvement during the study period. The presence of anti-CRP was analysed by enzyme-linked immunosorbent assay. The cut-off for positive anti-CRP test was set at the 95th centile of 100 healthy blood donor sera. Specificity of the anti-CRP antibody binding was evaluated by preincubating patient sera with either native or monomeric CRP. Disease activity was determined by the SLE disease activity index (SLEDAI), serum levels of CRP, anti-DNA antibodies, complement components and blood cell counts. Of 50 serum samples, 20 (40%) contained antibodies reactive with monomeric CRP, and 7 of 10 patients were positive on at least one occasion during the study. All patients with active lupus nephritis were positive for anti-CRP at flare. Frequent correlations between anti-CRP levels and disease activity measures were observed in anti-CRP-positive individuals. Accumulated anti-CRP data from all patients were positively correlated with SLEDAI scores and anti-DNA antibody levels, whereas significant inverse relationships were noted for complement factors C1q, C3 and C4, and for lymphocyte counts. This study confirms the high prevalence of anti-CRP autoantibodies in SLE and that the antibody levels are correlated with clinical and laboratory disease activity measures. This indicates that anti-CRP antibodies might have biological functions of pathogenetic interest in SLE. Further prospective clinical studies and experimental studies on effects mediated by anti-CRP antibodies are warranted

A subset of patients with systemic lupus erythematosus fails to degrade DNA from multiple clinically relevant sources

Patients with systemic lupus erythematosus (SLE) have a decreased ability to clear cell remnants and multiple deficiencies in the ability to degrade cellular chromatin have been linked to the disease. Since the discovery of neutrophil extracellular traps (NETs), a renewed interest has been sparked in this field of research with multiple studies reporting a decreased ability of patients with SLE to degrade NETs. In this study we extend these findings by investigating the ability of patients with SLE to degrade chromatin from multiple clinically relevant sources

Protein synthesis of the pro-inflammatory S100A8/A9 complex in plasmacytoid dendritic cells and cell surface S100A8/A9 on leukocyte subpopulations in systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9. Methods: Flow cytometry, confocal microscopy and real-time PCR of flow cytometry-sorted cells were used to measure cell surface S100A8/A9, intracellular S100A8/A9 and mRNA levels of S100A8 and S100A9, respectively. Results: Cell surface S100A8/A9 was detected on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and stimulation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex stimulation, pDCs up-regulated the cell surface S100A8/A9. SLE patients had also increased serum levels of S100A8/A9. Conclusions: Patients with SLE had increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE

Low production of reactive oxygen species in granulocytes is associated with organ damage in systemic lupus erythematosus

Introduction: Polymorphonuclear leukocytes (PMN) are main effector cells in the acute immune response. While the specific role of PMN in systemic lupus erythematosus (SLE) and autoimmunity is still unclear, their importance in chronic inflammation is gaining more attention. Here we investigate aspects of function, bone marrow release and activation of PMN in patients with SLE. Methods: The following PMN functions and subsets were evaluated using flow cytometry; (a) production of reactive oxygen species (ROS) after ex vivo stimulation with phorbol 12-myristate 13-acetate (PMA) or Escherichia coli (E. coli); (b) capacity to phagocytose antibody-coated necrotic cell material; (c) PMN recently released from bone marrow, defined as percentage of CD10(-)D16(low) in peripheral blood, and (d) PMN activation markers; CD11b, CD62L and C5aR. Results: SLE patients (n = 92) showed lower ROS production compared with healthy controls (n = 38) after activation ex vivo. The ROS production was not associated with corticosteroid dose or other immunotherapies. PMA induced ROS production was significantly reduced in patients with severe disease. In contrast, neither ROS levels after E. coli activation, nor the capacity to phagocytose were associated with disease severity. This suggests that decreased ROS production after PMA activation is a sign of changed PMN behaviour rather than generally impaired functions. The CD10(-)CD16(low) phenotype constitute 2% of PMN in peripheral blood of SLE patients compared with 6.4% in controls, indicating a decreased release of PMN from the bone marrow in SLE. A decreased expression of C5aR on PMN was observed in SLE patients, pointing towards in vivo activation. Conclusions: Our results indicate that PMN from SLE patients have altered function, are partly activated and are released abnormally from bone marrow. The association between low ROS formation in PMN and disease severity is consistent with findings in other autoimmune diseases and might be considered as a risk factor

Integration and fusion of standard automated perimetry and optical coherence tomography data for improved automated glaucoma diagnostics

<p>Abstract</p> <p>Background</p> <p>The performance of glaucoma diagnostic systems could be conceivably improved by the integration of functional and structural test measurements that provide relevant and complementary information for reaching a diagnosis. The purpose of this study was to investigate the performance of data fusion methods and techniques for simple combination of Standard Automated Perimetry (SAP) and Optical Coherence Tomography (OCT) data for the diagnosis of glaucoma using Artificial Neural Networks (ANNs).</p> <p>Methods</p> <p>Humphrey 24-2 SITA standard SAP and StratusOCT tests were prospectively collected from a randomly selected population of 125 healthy persons and 135 patients with glaucomatous optic nerve heads and used as input for the ANNs. We tested commercially available standard parameters as well as novel ones (fused OCT and SAP data) that exploit the spatial relationship between visual field areas and sectors of the OCT peripapillary scan circle. We evaluated the performance of these SAP and OCT derived parameters both separately and in combination.</p> <p>Results</p> <p>The diagnostic accuracy from a combination of fused SAP and OCT data (95.39%) was higher than that of the best conventional parameters of either instrument, i.e. SAP Glaucoma Hemifield Test (p < 0.001) and OCT Retinal Nerve Fiber Layer Thickness ≥ 1 quadrant (p = 0.031). Fused OCT and combined fused OCT and SAP data provided similar Area under the Receiver Operating Characteristic Curve (AROC) values of 0.978 that were significantly larger (p = 0.047) compared to ANNs using SAP parameters alone (AROC = 0.945). On the other hand, ANNs based on the OCT parameters (AROC = 0.970) did not perform significantly worse than the ANNs based on the fused or combined forms of input data. The use of fused input increased the number of tests that were correctly classified by both SAP and OCT based ANNs.</p> <p>Conclusions</p> <p>Compared to the use of SAP parameters, input from the combination of fused OCT and SAP parameters, and from fused OCT data, significantly increased the performance of ANNs. Integrating parameters by including a priori relevant information through data fusion may improve ANN classification accuracy compared to currently available methods.</p

Carbon-Based Nanoelectromechanical Devices

Carbon-based nanoelectromechanical devices are approaching applications in electronics. Switches based on individual carbon nanotubes deliver record low off-state leakage currents. Arrays of vertically aligned carbon nanotubes or nanofibers can be fabricated to constitute varactors. Very porous, low density arrays of quasi-vertically aligned arrays of carbon nanotubes behave mechanically as a single unit with very unusual material properties

Entanglement in Many-Body Systems

The recent interest in aspects common to quantum information and condensed matter has prompted a prosperous activity at the border of these disciplines that were far distant until few years ago. Numerous interesting questions have been addressed so far. Here we review an important part of this field, the properties of the entanglement in many-body systems. We discuss the zero and finite temperature properties of entanglement in interacting spin, fermionic and bosonic model systems. Both bipartite and multipartite entanglement will be considered. At equilibrium we emphasize on how entanglement is connected to the phase diagram of the underlying model. The behavior of entanglement can be related, via certain witnesses, to thermodynamic quantities thus offering interesting possibilities for an experimental test. Out of equilibrium we discuss how to generate and manipulate entangled states by means of many-body Hamiltonians.Comment: 61 pages, 29 figure

Low-density granulocytes are related to shorter pregnancy duration but not to interferon alpha protein blood levels in systemic lupus erythematosus

BACKGROUND: An increased risk of pregnancy complications is seen in women with systemic lupus erythematosus (SLE), but the specific immunopathological drivers are still unclear. Hallmarks of SLE are granulocyte activation, type I interferon (IFN) overproduction, and autoantibodies. Here we examined whether low-density granulocytes (LDG) and granulocyte activation increase during pregnancy, and related the results to IFNα protein levels, autoantibody profile, and gestational age at birth. METHODS: Repeated blood samples were collected during pregnancy in trimesters one, two, and three from 69 women with SLE and 27 healthy pregnant women (HC). Nineteen of the SLE women were also sampled late postpartum. LDG proportions and granulocyte activation (CD62L shedding) were measured by flow cytometry. Plasma IFNα protein concentrations were quantified by single molecule array (Simoa) immune assay. Clinical data were obtained from medical records. RESULTS: Women with SLE had higher LDG proportions and increased IFNα protein levels compared to HC throughout pregnancy, but neither LDG fractions nor IFNα levels differed during pregnancy compared to postpartum in SLE. Granulocyte activation status was higher in SLE relative to HC pregnancies, and it was increased during pregnancy compared to after pregnancy in SLE. Higher LDG proportions in SLE were associated with antiphospholipid positivity but not to IFNα protein levels. Finally, higher LDG proportions in trimester three correlated independently with lower gestational age at birth in SLE. CONCLUSION: Our results suggest that SLE pregnancy results in increased peripheral granulocyte priming, and that higher LDG proportions late in pregnancy are related to shorter pregnancy duration but not to IFNα blood levels in SLE

The role country of birth plays in receiving disability pensions in relation to patterns of health care utilisation and socioeconomic differences: a multilevel analysis of Malmo, Sweden

BACKGROUND: People of low socioeconomic status have worse health and a higher probability of being granted a disability pension than people of high socioeconomic status. It is also known that public and private general physicians and public and private specialists have varying practices for issuing sick leave certificates (which, if longstanding, may become the basis of disability pensions). However, few studies have investigated the influence of a patient's country of birth in this context. METHODS: We used multilevel logistic regression analysis with individuals (first level) nested within countries of birth (second level). We analysed the entire population between the ages of 40 and 64 years (n = 80 212) in the city of Malmo, Sweden, in 2003, and identified 73% of that population who had visited a physician at least once during that year. We studied the associations between individuals and country of birth socioeconomic characteristics, as well as individual utilisation of different kinds of physicians in relation to having been granted a disability pension. RESULTS: Living alone (OR(women )= 1.72, 95% CI: 1.62–1.82; OR(men )= 2.64, 95% CI: 2.46–2.83) and having limited educational achievement (OR(women )= 2.14, 95% CI: 2.00–2.29; OR(men )= 2.12, 95% CI: 1.98–2.28) were positively associated with having a disability pension. Utilisation of public specialists was associated with a higher probability (OR(women )= 2.11, 95% CI: 1.98–2.25; OR(men )= 2.16, 95% CI: 2.01–2.32) and utilisation of private GPs with a lower probability (OR(men )= 0.76, 95% CI: 0.69–0.83) of having a disability pension. However, these associations differed by countries of birth. Over and above individual socioeconomic status, men from middle income countries had a higher probability of having a disability pension (OR(men )= 1.61, 95% CI: 1.06–2.44). CONCLUSION: The country of one's birth appears to play a significant role in understanding how individual socioeconomic differences bear on the likelihood of receiving a disability pension and on associated patterns of health care utilisation